Myocarditis is an inflammatory disease of the myocardium. Approximately 65% of cases follow recent enterovirus infections and occur in males. As in humans, CVB3 infections cause severe myocarditis in male, but not virgin female mice. Androgens (progesterone and testosterone) increase virus receptor expression on cardiac myocytes while 17- beta-estradiol treatment does not. Since lymphocytes also express CVB3 receptors, we hypothesize that hormones might modulate lymphocyte expression of these molecules as well. Furthermore, enterovirus receptors often belong to immunoglobulin and integrin superfamilies, which have important signal transduction functions. Direct virus binding to normal lymphocytes causes rapid calcium flux and cytokine release within four hours of virus exposure. Cytokine release differs between male and female lymphocytes with male cells producing interferon (IFN)gamma and female cells producing interleukin (IL)- 10. We hypothesize that viruses, which have repetitive symmetry of the virus capsid, cross-link important cell surface molecules on lymphocytes and cause rapid non-antigen-specific lymphocyte activation. This initial activation with associated cytokine release determines subsequent innate and adaptive immune responses to the virus, such as CD4+ T helper (Th) cell response and development/survival of autoimmune CD8+ T cells in vivo. The Specific Aims of this application are to: 1) Determine virus receptor expression, binding avidity, activation potential and cytokine production on male and female lymphoid cells exposed to non-infectious virus; 2) Determine the effects of direct virus interaction and hormone signaling on CD8+alpha,beta T cell receptor (TCR)+ and gamma,delta TCR+ effector cell function and survival in vivo; and 3) Determine the effects of direct virus interaction and hormone signaling on virus-specific CD4+alpha,beta TCR+ response and survival in vivo. These studies may provide new insights as to how viruses affect developing host defense responses and how hormones can modulate this initial response.